Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α1-adrenoceptor antagonistic properties

Abstract: The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α1-adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione (7) and hydrochloride of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (10a) were solved using the X-ray diffraction method. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) were used to predict 3D structure of compounds 5a–18a using a crystal structure of 7. SAR analysis was performed on the basis of Barbaro’s pharmacophore model and structural properties of previously investigated α1-adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for α1-ARs in nanomolar range (40–290nM). The highest activities (K i <75nM) were observed for compounds possessing a 2-alkoxyphenylpiperazine fragment and two methoxy substituents at the benzylidene moiety. The results indicated that chemical properties, number and positions of substituents at the 5-arylidene fragment influenced the power of α1-affinities as follows: 3,4-di CH3O>2,4-di CH3O>4-Cl>2,3-di CH3O>H>4-N(CH3)2. [Copyright &y& Elsevier]